Drug abuse is a major public health problem contributing to cancer, infectious disease, and AIDS, partly through increased disease susceptibility of drug users. Drugs such as opioids can promote the high incidence of infectious disease and HIV seropositivity in drug users by functioning as cofactors to alter host immune function, incidence of infection, and eventual development of AIDS in this population. We plan to determine the mechanisms through which opioids produce effects on the immune system through identification of the central sites of action and opioid receptor subtypes involved, the demonstration of chemical and/or anatomic peripheral connections to immune system compartments, and the mechanisms of opioid immunoregulation at the level of the leukocyte. Opioids have many clinical uses, and understanding how drugs produce effects on the immune system allows the design and synthesis of novel non- peptide opioid analgesics devoid of immunosuppressive properties, as well as opioids with immunostimulatory potential. Thus, the diversity of the opioids provides a source of compounds with immunotherapeutic potential, as well as pharmacologic tools for investigation of how the immune system is naturally controlled and regulated by the brain. The specific aims are: A. To determine the opioid receptor-selective subtypes and CNS sites involved in centrally mediated opioid immunoregulation. We plan to inject opioid receptor subtype-selective agonists and antagonists peripherally and centrally to examine CNS sites regulating immune function, by measuring inhibition or activation of immune parameters such as proliferation, cytotoxic responses, cytokine production, and activation marker expression. B. To determine the peripheral pharmacologic mechanisms and pathways of centrally mediated opioid immunoregulation. We will employ a combination of pharmacologic antagonists of glucocorticoid and catecholamine action, analysis of blood ACTH, cortisone, and catecholamines, and denervation of lymphoid organs to investigate peripheral pathways connecting the CNS to the immune system. C. To determine the cellular mechanisms of centrally mediated opioid immunoregulation. We will examine functional changes such as cytotoxicity and proliferation, in lymphoid cell populations from various compartments, cell surface markers of lymphocyte activation, and cytokine production, as a function of opioid agonist and antagonist administration.